scholarly journals Genome-Wide Expression Profiling of the Response to Azole, Polyene, Echinocandin, and Pyrimidine Antifungal Agents in Candida albicans

2005 ◽  
Vol 49 (6) ◽  
pp. 2226-2236 ◽  
Author(s):  
Teresa T. Liu ◽  
Robin E. B. Lee ◽  
Katherine S. Barker ◽  
Richard E. Lee ◽  
Lai Wei ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Ergosterol Biosynthesis ◽  
Reverse Transcription Pcr ◽  
Expression Of Genes ◽  
Lipid Fatty Acid ◽  
Genes Encoding ◽  
Molecule Transport ◽  
Small Molecule Transport

ABSTRACT Antifungal agents exert their activity through a variety of mechanisms, some of which are poorly understood. We examined changes in the gene expression profile of Candida albicans following exposure to representatives of the four currently available classes of antifungal agents used in the treatment of systemic fungal infections. Ketoconazole exposure increased expression of genes involved in lipid, fatty acid, and sterol metabolism, including NCP1, MCR1, CYB5, ERG2, ERG3, ERG10, ERG25, ERG251, and that encoding the azole target, ERG11. Ketoconazole also increased expression of several genes associated with azole resistance, including CDR1, CDR2, IFD4, DDR48, and RTA3. Amphotericin B produced changes in the expression of genes involved in small-molecule transport (ENA21), and in cell stress (YHB1, CTA1, AOX1, and SOD2). Also observed was decreased expression of genes involved in ergosterol biosynthesis, including ERG3 and ERG11. Caspofungin produced changes in expression of genes encoding cell wall maintenance proteins, including the β-1,3-glucan synthase subunit GSL22, as well as PHR1, ECM21, ECM33, and FEN12. Flucytosine increased the expression of proteins involved in purine and pyrimidine biosynthesis, including YNK1, FUR1, and that encoding its target, CDC21. Real-time reverse transcription-PCR was used to confirm microarray results. Genes responding similarly to two or more drugs were also identified. These data shed new light on the effects of these classes of antifungal agents on C. albicans.

scholarly journals Flavones, Flavonols, and Glycosylated Derivatives—Impact on Candida albicans Growth and Virulence, Expression of CDR1 and ERG11, Cytotoxicity

2020 ◽  
Vol 14 (1) ◽  
pp. 27
Author(s):  
Marija Ivanov ◽  
Abhilash Kannan ◽  
Dejan S. Stojković ◽  
Jasmina Glamočlija ◽  
Ricardo C. Calhelha ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Infections ◽  
Ergosterol Biosynthesis ◽  
Fungal Virulence ◽  
Wide Range ◽  
Genes Encoding ◽  
Increasing Demand ◽  
Hyphal Formation ◽  
Further Development

Due to the high incidence of fungal infections worldwide, there is an increasing demand for the development of novel therapeutic approaches. A wide range of natural products has been extensively studied, with considerable focus on flavonoids. The antifungal capacity of selected flavones (luteolin, apigenin), flavonols (quercetin), and their glycosylated derivatives (quercitrin, isoquercitrin, rutin, and apigetrin) along with their impact on genes encoding efflux pumps (CDR1) and ergosterol biosynthesis enzyme (ERG11) has been the subject of this study. Cytotoxicity of flavonoids towards primary liver cells has also been addressed. Luteolin, quercitrin, isoquercitrin, and rutin inhibited growth of Candida albicans with the minimal inhibitory concentration of 37.5 µg/mL. The application of isoquercitrin has reduced C. albicans biofilm establishing capacities for 76%, and hyphal formation by yeast. In vitro treatment with apigenin, apigetrin, and quercitrin has downregulated CDR1. Contrary to rutin and apigenin, isoquercitrin has upregulated ERG11. Except apigetrin and quercitrin (90 µg/mL and 73 µg/mL, respectively inhibited 50% of the net cell growth), the examined flavonoids did not exhibit cytotoxicity. The reduction of both fungal virulence and expression of antifungal resistance-linked genes was the most pronounced for apigenin and apigetrin; these results indicate flavonoids’ indispensable capacity for further development as part of an anticandidal therapy or prevention strategy.

Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

2019 ◽  
Vol 15 (6) ◽  
pp. 648-658 ◽  
Author(s):  
Manzoor Ahmad Malik ◽  
Shabir Ahmad Lone ◽  
Parveez Gull ◽  
Ovas Ahmad Dar ◽  
Mohmmad Younus Wani ◽  
...  
Keyword(s):  
Schiff Base ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Infections ◽  
Total Sterol ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Ergosterol Biosynthesis ◽  
Dependent Manner ◽  
Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

scholarly journals Variable Expressions of Staphylococcus aureus Bicomponent Leucotoxins Semiquantified by Competitive Reverse Transcription-PCR

2000 ◽  
Vol 66 (9) ◽  
pp. 3931-3938 ◽  
Author(s):  
St�phane Bronner ◽  
Patricia Stoessel ◽  
Alain Gravet ◽  
Henri Monteil ◽  
Gilles Pr�vost
Keyword(s):  
Staphylococcus Aureus ◽  
Reverse Transcription ◽  
Regulatory System ◽  
Optimization Procedure ◽  
Reverse Transcription Pcr ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Specific Mrnas ◽  
Casamino Acids ◽  
Global Regulatory System

ABSTRACT A competitive reverse transcription-PCR method was developed for the semiquantitation of the expression of genes encoding bicomponent leucotoxins of Staphylococcus aureus, e.g., Panton-Valentine leucocidin (lukPV), gamma-hemolysin (hlgA and hlgCB), and LukE-LukD (lukED). The optimization procedure included RNA preparation; reverse transcription; the use of various amounts of enzymes, antisense primer, and RNA; and the final amplification chain reaction. Reproducible results were obtained, with sensitivity for detection of cDNA within the range of 1 mRNA/104 CFU to 102 mRNA/CFU, depending on the gene. Both specific mRNAs were more significantly expressed at the late-exponential phase of growth. Expression was about 100-fold higher in yeast extract-Casamino Acids-pyruvate medium than in heart infusion medium. Expression of the widely distributed gamma-hemolysin locus in the NTCC 8178 strain was around 10-fold diminished compared with that in the ATCC 49775 strain. Because of the lower level of hlgA expression, the corresponding protein, which is generally not abundant in culture supernatant, should be investigated for its contribution to the leucotoxin-associated virulence. The agr, sar, and agr sar mutant strains revealed a great dependence with regard to leucotoxin expression on the global regulatory system inS. aureus, except that expression of hlgA was not affected in the agr mutant.

scholarly journals Candida albicans Sterol C-14 Reductase, Encoded by the ERG24 Gene, as a Potential Antifungal Target Site

2002 ◽  
Vol 46 (4) ◽  
pp. 947-957 ◽  
Author(s):  
N. Jia ◽  
B. Arthington-Skaggs ◽  
W. Lee ◽  
C. A. Pierson ◽  
N. D. Lees ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Brefeldin A ◽  
Agricultural Applications ◽  
Mouse Model System ◽  
Cellular Inhibitors ◽  
Germ Tubes ◽  
Doubling Times

ABSTRACT The incidence of fungal infections has increased dramatically, which has necessitated additional and prolonged use of the available antifungal agents. Increased resistance to the commonly used antifungal agents, primarily the azoles, has been reported, thus necessitating the discovery and development of compounds that would be effective against the major human fungal pathogens. The sterol biosynthetic pathway has proved to be a fertile area for antifungal development, and steps which might provide good targets for novel antifungal development remain. The sterol C-14 reductase, encoded by the ERG24 gene, could be an effective target for drug development since the morpholine antifungals, inhibitors of Erg24p, have been successful in agricultural applications. The ERG24 gene of Candida albicans has been isolated by complementation of a Saccharomyces cerevisiae erg24 mutant. Both copies of the C. albicans ERG24 gene have been disrupted by using short homologous regions of the ERG24 gene flanking a selectable marker. Unlike S. cerevisiae, the C. albicans ERG24 gene was not required for growth, but erg24 mutants showed several altered phenotypes. They were demonstrated to be slowly growing, with doubling times at least twice that of the wild type. They were also shown to be significantly more sensitive to an allylamine antifungal and to selected cellular inhibitors including cycloheximide, cerulenin, fluphenazine, and brefeldin A. The erg24 mutants were also slightly resistant to the azoles. Most importantly, erg24 mutants were shown to be significantly less pathogenic in a mouse model system and failed to produce germ tubes upon incubation in human serum. On the basis of these characteristics, inhibitors of Erg24p would be effective against C. albicans.

scholarly journals Mds3 Regulates Morphogenesis in Candida albicans through the TOR Pathway

2010 ◽  
Vol 30 (14) ◽  
pp. 3695-3710 ◽  
Author(s):  
Lucia F. Zacchi ◽  
Jonatan Gomez-Raja ◽  
Dana A. Davis
Keyword(s):  
Candida Albicans ◽  
Ribosomal Proteins ◽  
Ph Sensing ◽  
Tor Pathway ◽  
Preferential Expression ◽  
Human Fungal Pathogen ◽  
Expression Of Genes ◽  
Mucosal Surfaces ◽  
Genes Encoding ◽  
Morphological Defects

ABSTRACT The success of Candida albicans as a major human fungal pathogen is dependent on its ability to colonize and survive as a commensal on diverse mucosal surfaces. One trait required for survival and virulence in the host is the morphogenetic yeast-to-hypha transition. Mds3 was identified as a regulator of pH-dependent morphogenesis that functions in parallel with the classic Rim101 pH-sensing pathway. Microarray analyses revealed that mds3Δ/Δ cells had an expression profile indicative of a hyperactive TOR pathway, including the preferential expression of genes encoding ribosomal proteins and a decreased expression of genes involved in nitrogen source utilization. The transcriptional and morphological defects of the mds3Δ/Δ mutant were rescued by rapamycin, an inhibitor of TOR, and this rescue was lost in strains carrying the rapamycin-resistant TOR1-1 allele or an rbp1Δ/Δ deletion. Rapamycin also rescued the transcriptional and morphological defects associated with the loss of Sit4, a TOR pathway effector, but not the loss of Rim101 or Ras1. The sit4Δ/Δ and mds3Δ/Δ mutants had additional phenotypic similarities, suggesting that Sit4 and Mds3 function similarly in the TOR pathway. Finally, we found that Mds3 and Sit4 coimmunoprecipitate. Thus, Mds3 is a new member of the TOR pathway that contributes to morphogenesis in C. albicans as a regulator of this key morphogenetic pathway.

scholarly journals Targeting adhesion in fungal pathogen Candida albicans

2020 ◽  
Author(s):  
Harlei Martin ◽  
Kevin Kavanagh ◽  
Trinidad Velasco-Torrijos
Keyword(s):  
Candida Albicans ◽  
Fungal Infections ◽  
Initial Step ◽  
Infection Process ◽  
Host Cells ◽  
Fungal Cell ◽  
Receptor Interactions ◽  
Genes Encoding ◽  
Invasive Infections ◽  
Wall Components

Fungal infections with increasing resistance to conventional therapies are a growing concern. Candida albicans is a major opportunistic yeast responsible for mucosal and invasive infections. Targeting the initial step of the infection process (i.e., C. albicans adhesion to the host cell) is a promising strategy. A wide variety of molecules can interfere with adhesion processes via an assortment of mechanisms. Herein, we focus on how small molecules disrupt biosynthesis of fungal cell wall components and membrane structure, prevent the localization of GPI-anchor proteins, inhibit production of enzymes involved in adhesion, downregulate genes encoding adhesins and competitively inhibit receptor interactions. As a result, adhesion of C. albicans to host cells is reduced, paving the way to new classes of antifungal agents.

Transcriptome Analysis of Listeria monocytogenes Grown on a Ready-to-Eat Meat Matrix

2011 ◽  
Vol 74 (7) ◽  
pp. 1104-1111 ◽  
Author(s):  
DONGRYEOUL BAE ◽  
MICHAEL R. CROWLEY ◽  
CHINLING WANG
Keyword(s):  
Listeria Monocytogenes ◽  
Virulence Factors ◽  
Microarray Data ◽  
Meat Products ◽  
Phospholipid Metabolism ◽  
Transcriptional Level ◽  
Cellular Processes ◽  
Reverse Transcription Pcr ◽  
Expression Of Genes ◽  
Genes Encoding

The contamination of ready-to-eat (RTE) meat products with Listeria monocytogenes is a major concern for the food industry. For a better understanding of the adaptation and survival ability of L. monocytogenes grown on turkey deli meat, the transcriptome of L. monocytogenes strain F2365 was determined with a microarray. Microarray data were validated with a quantitative real-time reverse transcription PCR assay. Based on the microarray data, 39 and 45 genes from L. monocytogenes were transcriptionally upregulated and down-regulated, respectively. The genes regulated at the transcriptional level were mainly involved in energy metabolism, fatty acid and phospholipid metabolism, biosynthesis of proteins, transport and binding proteins, DNA metabolism, cellular processes, and regulatory functions. No significant change was noted for the expression of genes encoding known virulence factors such as sigB, prfA, inlA, inlB, plcA, plcB, and hly. These results suggest that L. monocytogenes grown on RTE deli meat changes its transcription of proteins involved in its metabolic pathways to obtain an energy source or to adapt to environmental change without increasing the expression of virulence factors. The global transcriptome profiles provide a better understanding of the growth or adaptation of L. monocytogenes in RTE meat products.

scholarly journals Evaluation of the effects of sdiA, a luxR homologue, on adherence and motility of Escherichia coli O157 : H7

Microbiology ◽  
2010 ◽  
Vol 156 (5) ◽  
pp. 1303-1312 ◽  
Author(s):  
Vijay K. Sharma ◽  
Shawn M. D. Bearson ◽  
Bradley L. Bearson
Keyword(s):  
Escherichia Coli ◽  
Epithelial Cells ◽  
Mutant Strain ◽  
Regulatory Networks ◽  
Double Mutant ◽  
Negative Regulator ◽  
Wild Type ◽  
Reverse Transcription Pcr ◽  
Expression Of Genes ◽  
Genes Encoding

Quorum-sensing (QS) signalling pathways are important regulatory networks for controlling the expression of genes promoting adherence of enterohaemorrhagic Escherichia coli (EHEC) O157 : H7 to epithelial cells. A recent study has shown that EHEC O157 : H7 encodes a luxR homologue, called sdiA, which upon overexpression reduces the expression of genes encoding flagellar and locus of enterocyte effacement (LEE) proteins, thus negatively impacting on the motility and intimate adherence phenotypes, respectively. Here, we show that the deletion of sdiA from EHEC O157 : H7 strain 86-24, and from a hha (a negative regulator of ler) mutant of this strain, enhanced bacterial adherence to HEp-2 epithelial cells of the sdiA mutant strains relative to the strains containing a wild-type copy of sdiA. Quantitative reverse transcription PCR showed that the expression of LEE-encoded genes ler, espA and eae in strains with the sdiA deletions was not significantly different from that of the strains wild-type for sdiA. Similarly, no additional increases in the expression of LEE genes were observed in a sdiA hha double mutant strain relative to that observed in the hha deletion mutant. While the expression of fliC, which encodes flagellin, was enhanced in the sdiA mutant strain, the expression of fliC was reduced by several fold in the hha mutant strain, irrespective of the presence or absence of sdiA, indicating that the genes sdiA and hha exert opposing effects on the expression of fliC. The strains with deletions in sdiA or hha showed enhanced expression of csgA, encoding curlin of the curli fimbriae, with the expression of csgA highest in the sdiA hha double mutant, suggesting an additive effect of these two gene deletions on the expression of csgA. No significant differences were observed in the expression of the genes lpfA and fimA of the operons encoding long polar and type 1 fimbriae in the sdiA mutant strain. These data indicate that SdiA has no significant effect on the expression of LEE genes, but that it appears to act as a strong repressor of genes encoding flagella and curli fimbriae, and the alleviation of the SdiA-mediated repression of these genes in an EHEC O157 : H7 sdiA mutant strain contributes to enhanced bacterial motility and increased adherence to HEp-2 epithelial cells.

scholarly journals Ribonucleotide Reduction in Mycobacterium tuberculosis: Function and Expression of Genes Encoding Class Ib and Class II Ribonucleotide Reductases

2003 ◽  
Vol 71 (11) ◽  
pp. 6124-6131 ◽  
Author(s):  
Stephanie S. Dawes ◽  
Digby F. Warner ◽  
Liana Tsenova ◽  
Juliano Timm ◽  
John D. McKinney ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Class Ii ◽  
Growth Conditions ◽  
Small Subunit ◽  
Reverse Transcription Pcr ◽  
Hypoxic Conditions ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Class Ib

ABSTRACT Mycobacterium tuberculosis, the causative agent of tuberculosis, possesses a class Ib ribonucleotide reductase (RNR), encoded by the nrdE and nrdF2 genes, in addition to a putative class II RNR, encoded by nrdZ. In this study we probed the relative contributions of these RNRs to the growth and persistence of M. tuberculosis. We found that targeted knockout of the nrdF2 gene could be achieved only in the presence of a complementing allele, confirming that this gene is essential under normal, in vitro growth conditions. This observation also implied that the alternate class Ib small subunit encoded by the nrdF1 gene is unable to substitute for nrdF2 and that the class II RNR, NrdZ, cannot substitute for the class Ib enzyme, NrdEF2. Conversely, a ΔnrdZ null mutant of M. tuberculosis was readily obtained by allelic exchange mutagenesis. Quantification of levels of nrdE, nrdF2, nrdF1, and nrdZ gene expression by real-time, quantitative reverse transcription-PCR with molecular beacons by using mRNA from aerobic and O2-limited cultures showed that nrdZ was significantly induced under microaerophilic conditions, in contrast to the other genes, whose expression was reduced by O2 restriction. However, survival of the ΔnrdZ mutant strain was not impaired under hypoxic conditions in vitro. Moreover, the lungs of B6D2/F1 mice infected with the ΔnrdZ mutant had bacterial loads comparable to those of lungs infected with the parental wild-type strain, which argues against the hypothesis that nrdZ plays a significant role in the virulence of M. tuberculosis in this mouse model.

Raynaud's Phenomenon of the Nipples: An Elusive Diagnosis

2007 ◽  
Vol 23 (2) ◽  
pp. 191-193 ◽  
Author(s):  
Carolyn Morino ◽  
Susan M. Winn
Keyword(s):  
Candida Albicans ◽  
Case Report ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Raynaud’S Phenomenon ◽  
Raynaud's Phenomenon

Pain and throbbing of the nipples associated with Raynaud's phenomenon often mimics yeast or fungal infections. Breastfeeding mothers with Raynaud's of the nipples are often treated inappropriately for organisms such as Candida Albicans with topical or systemic antifungal agents. This case report describes the eventual diagnosis of Raynaud's phenomenon of the nipples in a breastfeeding mother who was initially treated for yeast. J Hum Lact. 23(2):191-193.

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